Domain tethering impacts dimerization and DNA-mediated allostery in the human transcription factor FoxP1

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dc.contributor.authorCruz, Perla
dc.contributor.authorParedes, Nicolas
dc.contributor.authorAsela, Isabel
dc.contributor.authorKolimi, Narendar
dc.contributor.authorMolina, Jose Alejandro
dc.contributor.authorRamirez-Sarmiento, Cesar A.
dc.contributor.authorGoutam, Rajen
dc.contributor.authorHuang, Gangton
dc.contributor.authorMedina, Exequiel
dc.contributor.authorSanabria, Hugo
dc.date.accessioned2025-01-20T20:08:54Z
dc.date.available2025-01-20T20:08:54Z
dc.date.issued2023
dc.description.abstractTranscription factors are multidomain proteins with specific DNA binding and regulatory domains. In the human FoxP subfamily (FoxP1, FoxP2, FoxP3, and FoxP4) of transcription factors, a 90 residue-long disordered region links a Leucine Zipper (ZIP)-known to form coiled-coil dimers-and a Forkhead (FKH) domain-known to form domain swapping dimers. We used replica exchange discrete molecular dynamics simulations, single-molecule fluorescence experiments, and other biophysical tools to understand how domain tethering in FoxP1 impacts dimerization at ZIP and FKH domains and how DNA binding allosterically regulates their dimerization. We found that domain tethering promotes FoxP1 dimerization but inhibits a FKH domain-swapped structure. Furthermore, our findings indicate that the linker mediates the mutual organization and dynamics of ZIP and FKH domains, forming closed and open states with and without interdomain contacts, thus highlighting the role of the linkers in multidomain proteins. Finally, we found that DNA allosterically promotes structural changes that decrease the dimerization propensity of FoxP1. We postulate that, upon DNA binding, the interdomain linker plays a crucial role in the gene regulatory function of FoxP1.
dc.fuente.origenWOS
dc.identifier.doi10.1063/5.0138782
dc.identifier.eissn1089-7690
dc.identifier.issn0021-9606
dc.identifier.urihttps://doi.org/10.1063/5.0138782
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/91948
dc.identifier.wosidWOS:001017167500006
dc.issue.numero19
dc.language.isoen
dc.revistaJournal of chemical physics
dc.rightsacceso restringido
dc.subject.ods15 Life on Land
dc.subject.odspa15 Vida de ecosistemas terrestres
dc.titleDomain tethering impacts dimerization and DNA-mediated allostery in the human transcription factor FoxP1
dc.typeartículo
dc.volumen158
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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